The disease state referred to as glaucoma is characterized by a permanent loss of visual function due to irreversible damage to the optic nerve. The several morphologically or functionally distinct types of glaucoma are typically characterized by elevated IOP, which is considered to be causally related to the pathological course of the disease. Ocular hypertension is a condition wherein intraocular pressure is elevated, but no apparent loss of visual function has occurred; such patients are considered to be at high risk for the eventual development of the visual loss associated with glaucoma. Some patients with glaucomatous field loss have relatively low intraocular pressure. These normotension or low tension glaucoma patients can also benefit from agents that lower and control IOP. If glaucoma or ocular hypertension is detected early and treated promptly with medications that effectively reduce elevated intraocular pressure, loss of visual function or its progressive deterioration can generally be ameliorated.
Drug therapies that have proven to be effective for the reduction of intraocular pressure include both agents that decrease aqueous humor production and agents that increase the outflow facility. Such therapies are in general administered by one of two possible routes, topically (direct application to the eye) or orally. However, pharmaceutical ocular anti-hypertension approaches have exhibited various undesirable side effects. For example, miotics such as pilocarpine can cause blurring of vision, headaches, and other negative visual side effects. Systemically administered carbonic anhydrase inhibitors can also cause nausea, dyspepsia, fatigue, and metabolic acidosis. Certain prostaglandins cause hyperemia, ocular itching, and darkening of eyelashes and periorbital tissues. Further, certain beta-blockers have increasingly become associated with serious pulmonary side-effects attributable to their effects on beta-2 receptors in pulmonary tissue. Sympathomimetics cause tachycardia, arrhythmia and hypertension. Such negative side-effects may lead to decreased patient compliance or to termination of therapy such that normal vision continues to deteriorate. Additionally, there are individuals who simply do not respond well when treated with certain existing glaucoma therapies. There is, therefore, a need for other therapeutic agents that control IOP.
The small rho GTPases are involved in many cellular functions including cell adhesion, cell motility, cell migration, and cell contraction. One of the main effectors of the cellular functions associated with this class of proteins is rho-associated coiled-coil-forming protein kinase (rho kinase) which appears to have an important role in the regulation of force and velocity of smooth muscle contraction, tumor cell metastasis and inhibition of neurite outgrowth. Rho kinase is a serine/threonine protein kinase that exists in two isoforms: ROCK1 (ROKβ) and ROCK2 (ROKα) [N. Wettschureck, S. Offersmanns, Journal of Molecular Medicine 80:629-638, 2002; M. Uehata et al., Nature 389:990-994, 1997; T. Ishizaki et al., Molecular Pharmacology 57:976-983, 2000, C. Loge et al., Journal of Enzyme Inhibition and Medicinal Chemistry 17:381-390, 2002].
It has been found that certain inhibitors of rho kinase effectively lower and control normal and elevated IOP [M. Honjo, et al., Investigative Ophthalmology and Visual Science 42:137-144, 2001; M. Honjo et al., Archives of Ophthalmology 119:1171-1178, 2001; P.V. Rao et. al., Investigative Ophthalmology and Visual Science 42:10291690, 2001; M. Waki, Current Eye Research 22:47-474, 2001; B. Tian et al., Archives of Ophthalmology 122:1171-1177, 2004]. Rho kinase inhibitors such as H-7 and Y-27632 inhibit ciliary muscle contraction and trabecular cell contraction, effects that may be related to the ocular hypotensive effect of this class of compounds [H. Thieme et al., Investigative Ophthalmology and Visual Science 41:4240-4246, 2001; C. Fukiage et al., Biochemical and Biophysical Research Communications 288:296-300, 2001].
Compounds that act as rho kinase inhibitors are well known and have shown a variety of utilities. Pyridine, indazole, and isoquinoline compounds that have rho kinase activity are described by Takami et al., Biorganic and Medicinal Chemistry 12:2115-2137, 2004. U.S. Pat. Nos. 6,218,410 and 6,451,825 disclose the use of rho kinase inhibitors for the treatment of hypertension, retinopathy, cerebrovascular contraction, asthma, inflammation, angina pectoris, peripheral circulation disorder, immature birth, osteoporosis, cancer, inflammation, immune disease, autoimmune disease and the like. U.S. Pat. No. 6,794,398 describes the use of a compound with rho kinase activity for the prevention or treatment of liver diseases. U.S. Pat. No. 6,720,341 describes the use of compounds with rho kinase activity for the treatment of kidney disease. WO 99/23113 describes the use of rho kinase inhibitors to block the inhibition of neurite outgrowth. WO 03/062227 describes 2,4-diaminopyrimidine derivatives as rho kinase inhibitors. WO 03/059913 describes bicyclic 4-aminopyrimidine analogs as rho kinase inhibitors. WO 02/100833 describes heterocyclic compounds as rho kinase inhibitors. WO 01/68607 describes amide derivatives as rho kinase inhibitors. WO 04/024717 describes amino isoquinoline derivatives as rho kinase inhibitors. WO 04/009555 describes 5-substituted isoquinoline derivatives as rho kinase inhibitors useful for treating glaucoma, bronchial asthma and chronic obstructive pulmonary disease. EP1034793 describes the use of rho kinase inhibitors for the treatment of glaucoma.
U.S. Pat. Nos. 6,503,924, 6,649,625, and 6,673,812 disclose the use of amide derivatives that are rho kinase inhibitors for the treatment of glaucoma. U.S. Pat. Nos. 5,798,380 and 6,110,912 disclose a method for treating glaucoma using serine/threonine kinase inhibitors. U.S. Pat. No. 6,586,425 describes a method for treating glaucoma using serine/threonine kinase inhibitors. U.S. patent application Publication No. 2002/0045585 describes a method for treating glaucoma using serine/threonine kinase inhibitors.
The following references disclose the activity of isoquinoline sulfonamide analogs as rho kinase inhibitors: Y. Sasaki, Cellular Biology Molecular Letters 6:506, 2001; S. Satoh et al., Life Sciences 69:1441-1453, 2001; Y. Sasaki, Pharmacology and Therapeutics 93:225-232, 2002; C. Loge et al., Journal of Enzyme Inhibition and Medicinal Chemistry 18:127-138. The use of certain isoquinolinesulfonyl compounds for the treatment of glaucoma has been disclosed in U.S. Pat. Nos. 6,271,224 and 6,403,590. Also, WO 04/000318 describes the use of amino-substituted monocycles as AKT-1 kinase modulators.
Several publications have described the synthesis of pyrazines. WO 04/084824 describes the preparation of biaryl substituted 6-membered heterocycles for use as sodium channel blockers. WO 04/085409 describes the preparation of libraries of compounds, including pyrazines, that are capable of binding to the active site of protein kinase. Other publications involving methods of pyrazine synthesis include: Sato et al., Journal of Chemical Research 7:250-1, 1997; Sato et al., Synthesis 9:931-4, 1994; Sato, Journal of the Chemical Society 7:885-8, 1994; Sato, Journal of Organic Chemistry 43(2):341-3, 1978; Adachi, J et al., Journal of Organic Chemistry 37(2):221-5, 1972.